Evidence suggests that patients with diabetes have lower concentrations of reduced glutathione (GSH) indicative of impaired antioxidant defenses. Cataracts and retinopathy have been linked to impaired glutathione status. The mechanisms responsible for glutathione depletion in the diabetic state have not been established. It is reasonable to propose that a dual mechanism is operative in which the peroxidative stress associated with the disease leads to accelerated loss of GSH while the ability to synthesize GSH in sufficient quantities to meet the increased need is compromised because of decreased availability of the precursor amino acids cysteine and glycine. Using stable isotope techniques, we will measure the rate of synthesis of glutathione and relate this measurement to the syntheses of cysteine and glycine in adult patients with diabetes and in healthy adults. Eight NIDDM, 8 IDDM, and 16 healthy controls matched for age with the NIDDM and IDDM will be admitted on 4 occasions: after usual diet (no supplementation), after supplementation with cysteine, after supplementation with glycine, and after supplementation with both glycine and cysteine. During each occasion stable isotope and mass spectometry techniques will be used to determine cysteine, glycine and leucine kinetics as well as the rate of synthesis of erythrocyte and leukocyte glutathione. These measurements will be repeated after dietary supplementation with glycine, cysteine, and glycine plus cysteine. Thus far, we have enrolled 5 diabetic patients and 2 controls. Preliminary data shows that compared to controls, diabetics have a higher concentration of hydroperoxides, and lower lymphocyte GSH concentration as well as synthesis rate. With cysteine supplementaion GSH concentration and absolute synthesis rate increased twelve fold. This suggests that cysteine supplementaion can improve GSH homeostasis.